Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice
Felicia Chen, Hector Marquez, Youn-Kyung Kim, Jun Qian, Fengzhi Shao, Alan Fine, William W. Cruikshank, Loredana Quadro, Wellington V. Cardoso
Felicia Chen, Hector Marquez, Youn-Kyung Kim, Jun Qian, Fengzhi Shao, Alan Fine, William W. Cruikshank, Loredana Quadro, Wellington V. Cardoso
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Research Article Pulmonology

Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice

Abstract

There is increasing evidence that vitamin A deficiency in utero correlates with abnormal airway smooth muscle (SM) function in postnatal life. The bioactive vitamin A metabolite retinoic acid (RA) is essential for formation of the lung primordium; however, little is known about the impact of early fetal RA deficiency on postnatal lung structure and function. Here, we provide evidence that during murine lung development, endogenous RA has a key role in restricting the airway SM differentiation program during airway formation. Using murine models of pharmacological, genetic, and dietary vitamin A/RA deficiency, we found that disruption of RA signaling during embryonic development consistently resulted in an altered airway SM phenotype with markedly increased expression of SM markers. The aberrant phenotype persisted postnatally regardless of the adult vitamin A status and manifested as structural changes in the bronchial SM and hyperresponsiveness of the airway without evidence of inflammation. Our data reveal a role for endogenous RA signaling in restricting SM differentiation and preventing precocious and excessive SM differentiation when airways are forming.

Authors

Felicia Chen, Hector Marquez, Youn-Kyung Kim, Jun Qian, Fengzhi Shao, Alan Fine, William W. Cruikshank, Loredana Quadro, Wellington V. Cardoso

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Figure 1

Disruption of RA signaling leads to aberrant expression of SM markers in mouse embryonic lung explant (A–H) and MLg cell (I–L) cultures.

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Disruption of RA signaling leads to aberrant expression of SM markers in...
BMS-treated RARElacZ lungs (48 hours): significant downregulation of Rarb and RARElacZ (A) and increased expression of Tagln and Myh11 (F) and their products SM22α and SMMHC2, respectively) (G). (B–E) Whole-mount ISH of Acta2 (B and C) and Myh11 (D and E) increased signals in the mesenchyme of proximal (pr) and distal (di) airways in BMS-treated lungs compared with those of controls (arrowheads). Strong ectopic Acta2 expression was seen in stalks of distal buds in BMS-treated lungs. (H) Increased ratio of pMYL2/tMYL2 in BMS-treated lungs. (I) PCR detection of RA pathway components in MLg cells: RA-synthesizing enzymes (ALDH1A1, -2, and -3) and RA receptors (RARα, RARβ, and RARγ). (J–L) BMS treatment (24 hours) disrupted RA signaling (downregulation of Rarb) and increased expression of SM marker genes (Tagln and Myh11) and products (SM22α) and of the pMYL2/tMYL2 ratio. (A, F, I, and K) PCR and (G, H, and L) Western blot analysis. n = 3–4 per condition. *P < 0.05. tr, trachea. Scale bar: 200 μm.